Mechanistic studies of FcRn inhibitors for the treatment of IgG-mediated diseases

描述（由申请方提供）：体内免疫球蛋白G（IgG）水平的调节是体液免疫的一个基本方面。该过程中的核心参与者是非经典Fc受体FcRn，其在细胞内和跨细胞转运IgG并将其从溶酶体降解中拯救出来。本申请涉及设计用于抑制FcRn的补救功能的工程化抗体的机制研究。我们的方法是改造Fc片段，使其竞争性抑制野生型IgG与FcRn的结合，从而增强其降解。这种工程抗体，或Abdegs（“增强IgG降解的抗体”），可用于降低小鼠中的IgG水平。因此，Abdegs有望作为抗体介导的疾病中IgG清除和诱导IgG-药物或IgG-毒素复合物消除的治疗剂。然而，迄今为止，Abdeg活性的机制和性质的特征很差。例如，尚未充分理解Abdeg-FcRn相互作用的生物物理性质如何与抑制活性相关。Abdegs治疗IgG介导的自身免疫的疗效也未进行分析。我们的实验旨在解决这些和其他问题，并将涉及使用体外和体内鼠系统。本研究的具体目的是：1.使用体外系统了解Fc-FcRn相互作用性质如何影响FcRn功能; 2.分析具有不同性质的潜在Abdegs对内源性IgG水平的影响; 3.分析Abdegs对小鼠类风湿关节炎模型的作用。这种在动物模型中进行的全面机制研究构成了我们长期研究目标的重要组成部分，即使用Abdegs治疗人类疾病。此外，该项目应提供有价值的洞察到调节体内IgG的运输和动力学的分子机制。

DESCRIPTION (provided by applicant): The regulation of immunoglobulin G (IgG) levels in vivo represents a fundamental aspect of humoral immunity. A central player in this process is the non-classical Fc receptor, FcRn, that transports IgGs within and across cells and salvages them from lysosomal degradation. The current application is directed towards mechanistic studies of engineered antibodies that are designed to inhibit the salvage function of FcRn. Our approach is to engineer Fc fragments so that they competitively inhibit the binding of wild type IgGs to FcRn and thereby enhance their degradation. Such engineered antibodies, or Abdegs (for `antibodies that enhance IgG degradation'), can be used to lower IgG levels in mice. As such, Abdegs hold promise as therapeutics for the clearance of IgGs in antibody-mediated diseases and in inducing the elimination of IgG-drug or IgG-toxin complexes. However, to date, the mechanisms and properties of Abdeg activity are poorly characterized. For example, it is not well understood how the biophysical nature of Abdeg-FcRn interactions correlates with inhibitory activity. The efficacy of Abdegs in the treatment of IgG-mediated autoimmunity has also not been analyzed. Our experiments are designed to address these and other questions, and will involve the use of in vitro and in vivo murine systems. The Specific aims of the current study are: 1. To understand how Fc-FcRn interaction properties impact FcRn function using in vitro systems; 2. To analyze the effects of potential Abdegs with distinct properties on endogenous IgG levels; 3. To analyze the effects of Abdegs in murine models of rheumatoid arthritis. This comprehensive mechanistic study in animal models constitutes a crucial component of our longer term research goal, which is to use Abdegs for the treatment of human disease. In addition, this project should provide valuable insight into the molecular mechanisms that regulate the transport and dynamics of IgGs in vivo.